Accumulating evidence has suggested the binding of Cu(II) to certain important proteins as a general feature in the neuropathology of many neurodegenerative disorders including prion diseases. These diseases are thought to be caused by the accumulation of a post-translationally modified formed of the normal cellular prion proteins. Although little is known about the exact function of the normal prion, it has been demonstrated that these proteins bind specifically to exogenous Cu(II) both in vivo and in vitro. The physiological significance of prion's ability to bind Cu(II) has been related to the control of copper homeostasis and the modulation of copper/zinc superoxide dismutase (CuZnSOD) activity in neurons. Surprisingly, the molecular mechanism of prion's ability to control these delicate neurological processes remains unclear to date. The long-term goal of this investigation is to elucidate the molecular basis of the interactions between prion proteins and CuZnSOD system and to delineate the role of prion-Cu(II) complexes in controlling copper homeostasis using the octarepeat peptides in prion proteins as a structural model. In aim 1 ligands involved in Cu(II) binding to and the possible structural changes of the octapeptide inj prion protein upon Cu(II) binding will be evaluated. This will be accomplished by nuclear magnetic resonance detection of the unique signal changes on Cu(II) binding and determination of the three- dimensional structure of the octapeptide as a function of added Cu(II). AIM 2 is designed to locate the sources that supply Cu(II) for binding to the prion peptide. We propose that the prion peptide captures its Cu(II) by sequestering the metal ions from certain copper enzymes that are critical to normal brain development and function, as there is no free Cu(II) available in vivo. Aim 3 will focus on the molecular mechanism of the modulation of CuZnSOD activity by prion peptides. This will be fulfilled by the structural elucidation of our postulated protein-peptide complex between prion peptide and CuZnSOD. Aim 4 is directed to depict the mechanisms of the interaction between prion peptides and some selected metalloporphyrins that demonstrated potential application in the treatment of prion diseases. The results of the proposed studies will provide a better understanding of the role of prion-copper complexes in the nervous system and will likely lead to the identification of additional neurodegenerative processes associated with copper homeostasis and provide insights into the development of therapeutic options.